In 1974, it was discovered that echinocandin compounds possess excellent antibacterial activity. Thereafter, many semisynthetic echinocandin compounds have been studied for their pharmacologic activities. In 2001, caspofungin was approved by US FDA, which represents the landmark for the research of antifungal medicaments. Caspofungin, the chemical structure of which is shown by Formula 1, represents a broad-spectrum and low-toxic medicament with unique action site:

Caspofungin analogs and the preparation of Caspofungin have been described in WO94/21677, WO96/24613, U.S. Pat. No. 5,552,521, WO097/47645, U.S. Pat. No. 5,936,062, WO02/083713, J. Org. Chem., 2007, 72, 2335-2343, CN101792486A, CN101648994A, WO2010008493A2, US2010168415A1, EP1785432, WO2010064219A1, WO2009158034A1, WO2009151341A1 and WO2010108637A1. The solvent residue and salt residue in Caspofungin should be strictly limited in the form of injections. However, caspofungin has poor stability, therefore, for preventing caspofungin from degrading, special methods are generally used to remove the residual solvent in it.
Methods for drying caspofungin using humid nitrogen have been reported in J. Org. Chem., 2007, 72, 2335-2343, U.S. Pat. No. 5,552,521, U.S. Pat. No. 5,936,062, WO96/24613 and EP1785432. However, there are some disadvantages for these methods, such as high cost, poor reproducibility, huge waste of nitrogen, and high residue of solvent, which do not comply with the quality requirement of medicaments.
Methods for drying caspofungin by lyophilization have been reported in WO94/21677, WO97/47645, CN101792486A, US2010168415A1, CN101648994A and WO2009158034A1. Amorphous caspofungin is obtained by the methods, and the disadvantages of which are poor stability and high solvent residue. The methods could hardly meet the requirements for industrialization due to the high cost, great energy consumption, low efficiency, and the limited productivity.
Spray drying method has been reported in WO2010008493A2, wherein a solution is sprayed into droplets in hot air flow, thereby evaporating the water or solvent contained in the solution rapidly. However, upon research, the present inventors have found that the resulting product is still amorphous caspofungin with poor stability; and the solvents, such as ethanol and ethyl acetate can not be removed thoroughly; and the solvent residue greatly exceeds the limit. Moreover, the method is unsuitable for industrialization due to the high cost for the necessary equipments, and the limitation of production scale.
The method for drying caspofungin by vacuum drying has been reported in WO2009151341A1. During the early stage of drying, the organic solvent contained in the sample can be readily removed; however, crystal lattice of the sample will gradually close with the reduction of residual solvent, resulting in the solvent retention in the crystal lattice. In the late stage of drying, crystal lattice of the sample will totally close, resulting in the solvent being retained in the crystal lattice permanently and unable to be removed. Additionally, during the procedure of drying, the stability of sample will decrease with the reduction of water content, therefore, the sample will degrade and caspofungin with high purity can not be obtained.
Salting-out crystallization of caspofungin has been reported in WO2010108637A1. The residual solvent is not present in the caspofungin obtained by the method, however, the content of salt in the product will inevitably exceed the limit, and the sample will degrade during the crystallization, therefore, the purity of product will be reduced, and the product can not be used as raw material for market supply or for the preparation of pharmaceutical formulation.
According to ICH (International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use), the residual solvent in drug is defined as volatile organic compounds produced or used during the production of raw medicine or excipients or the preparation of formulation, which can not be removed thoroughly. In the Guideline, the residual solvent is classified according to the harm extent, under the conditions for ensuring the safety of human, the acceptable amount, i.e., limit, of residual solvent is established, and the toxicologically acceptable level of residual solvent is proposed.
Generally, many solvents, such as tetrahydrofuran, acetonitrile, methanol, ethyl acetate and ethanol, will be used in the current process for producing caspofungin. However, the caspofungin product prepared by the routine methods said above can not comply with the requirements of residual solvent stipulated in ICH (see ICH Q3C).
Therefore, there are defects for each current preparation method for caspofungin, such as high cost for instrument, limited production scale, difficulties in operation and unsuitability for industrialization. The resulting product has poor stability, therefore, it should be stored below −70° C., which will result in difficulties in transportation of product and industrialization, and will restrict the production scale of industrialization. Therefore, it is urgent to develop a preparation method for caspofungin or salts thereof, and said method can efficiently remove the residual solvent in caspofungin, prevent caspofungin from degrading, and is suitable for industrialization, thereby obtaining caspofungin or salts thereof which is stable and with low solvent residue and complies with the medical standards.